The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review

J Psychiatr Res. 2019 Jan:108:57-83. doi: 10.1016/j.jpsychires.2018.07.006. Epub 2018 Jul 21.


Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, despite the great efforts and resources invested therewith. We performed a comprehensive review of the literature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several promising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia.

Keywords: Clinical trials; Dopamine; Experimental treatments; Glutamate; Novel therapeutics; Schizophrenia.

Publication types

  • Review

MeSH terms

  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Clinical Trials as Topic
  • Humans
  • Neurotransmitter Agents / adverse effects
  • Neurotransmitter Agents / pharmacology
  • Neurotransmitter Agents / therapeutic use*
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / metabolism
  • Receptors, Neurotransmitter / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism


  • Antipsychotic Agents
  • Neurotransmitter Agents
  • Receptors, Neurotransmitter